Polychlorinated biphenyls (PCB's) are widespread and persistent environmental pollutants of demonstrated toxicity for man and animals. They are fetotoxic and may be carcinogenic. The mechanism of PCB toxicity has not yet been elucidated, but there is evidence that PCB's can be metabolized to epoxide intermediates and bind covalently to liver macromolecules. We plan to investigate the role of covalent binding and mixed function oxidase activity in producing PCB toxicity, using a chick embryo model system. We will compare the Km and Vmax for covalent binding of PCB's to liver microsomes in vitro, with PCB production in vivo of hepatotoxicity as determined histologically, induction of mixed function oxidase activity and covalent binding. We will compare effects of PCB congeners differing in degrees of chlorination and isomeric form to delineate structural requirements for PCB production of toxicity, covalent binding and mixed function oxidase induction. We will examine the effects of inducers and inhibitors of mixed function oxidase on PCB covalent binding and hepatotoxicity. Changes in hepatotoxicity and covalent binding of the PCB's and in hepatic mixed function oxidase activity during embryonic development will be evaluated and compared. We expect thereby to learn whether covalent binding is associated with hepatotoxicity for some PCB's or PCB's in general, whether the extent of covalent binding and hepatotoxicity is affected by hepatic mixed function oxidase activity and whether PCB binding and susceptibility to PCB toxicity change during embryonic development. In complementary studies we will examine the Km and Vmax for the covalent binding of PCB's in vitro to human fetal liver and adrenal. We will compare the amount of binding and the mixed function oxidase activity of the tissues to learn whether individual differences in fetal tissue mixed function oxidase activity determine the amount of covalent binding of PCB's in individual abortuses. We will also examine changes in binding during mid-trimester fetal development and the influence of maternal cigarette smoking on the binding of PCB's to human fetal tissues. We expect that these studies will improve our ability to assess potential risks of chemical toxicity in human fetal tissues.